Part 1: Abemaciclib Shows Efficacy in High-Risk Early Breast Cancer

Lowell Hart, MD, FACP

Scientific Director of Clinical Research

Florida Cancer Specialists & Research Institute

Associate Professor

Wake Forest School of Medicine

Targeted Oncology^TM: Could you describe the design of the monarchE trial?

LOWELL HART, MD: The monarchE trial [NCT03155997] was divided into 2 cohorts of patients.¹ All the patients had lymph node-positive breast cancer. Cohort 1 was based on the high-risk clinical characteristics: more than 4 nodes or 1 to 3 nodes, and either grade 3 or T3-sized tumor, 5 cm or more. Cohort 2 was based on the Ki-67. So that was 1 to 3 nodes and not grade 3 or not greater than 5 cm. So, basically a smaller-sized tumor but 1 to 3 nodes positive and high Ki-67.

This was a large trial with over 5000 patients and they all received either standard endocrine therapy, they can have had neoadjuvant or adjuvant chemotherapy. They allowed premenopausal or postmenopausal women into the study. Patients received standard of care endocrine therapy alone or endocrine therapy with abemaciclib [Verzenio] standard doses 150 mg twice a day for 2 years. And then they’ve been followed up since then.

This study finished and now the data have been gradually coming out. Patients were stratified based on whether they had chemotherapy or not and whether they were premenopausal or postmenopausal disease.

What did the patient population look like in this trial?

There was further follow-up, which comes out to over 2 years, and about 3 out of 4 [patients] completed their treatments and 90% of them are off study at this point.² The results are more mature than they were before.

The question has always come up about why the [PALLAS trial (NCT02513394)] palbociclib [Ibrance] adjuvant trials were negative and whether it’s due to the fact it’s a weaker drug or if the patient population was not as high-risk.³

In this trial, about 60% of the patients had 4 or more nodes positive. A good number of patients had higher Ki67 levels, but there were about a third of the patients that had low Ki67s in this trial. There were about 40% of patients who were premenopausal in the trial. Because these are high-risk patients with node-positive disease, about 58% had adjuvant chemotherapy.

Most of these were in the either early postmenopausal or late pre-menopausal years, which is common in these trials. Those were the patients that tend to get on the trial, but that is a little bit younger than the average patient that walks into our offices, especially where I practice in Florida.

I think they picked a good population of patients to study. They certainly were high-risk patients and most of the patients that were offered to enroll in this trial chose to participate.

What was the efficacy of abemaciclib found in the trial based on invasive disease-free survival (IDFS)?

The IDFS benefit after 2 years of treatment and an extra year of follow-up afterwards was 88.8% if patients received abemaciclib and 83.4% if they received placebo. That is about a 5.4% difference, which comes out to about a 30% reduction in IDFS.

We found a significant reduction in the chance of having an invasive event at the 3-year mark. The Kaplan-Meier curve seems to be getting wider apart [from endocrine therapy] as time goes by, though these are not the final data. I think it is encouraging that the abemaciclib treatment ended at 24 months but the curves are still getting wider apart at 36 months, so it looks to me like [its efficacy] is real.²

In the subgroup analysis, some groups are small so their confidence interval is greater than 1, but in general, everything suggests that the addition of the abemaciclib is helpful in both patients who were premenopausal and postmenopausal. The same seems to be true for whether they got neoadjuvant chemotherapy or they didn’t. There’s very few patients with histological grade 1 disease so that’s going to overlap by a lot.

What was found regarding distant relapse-free survival (DRFS)?

The DRFS is opposed to any event the IDFS curve which could have local recurrence there. The results of the DRFS were very similar. There was [a 31.3%] reduction [in risk of developing a DRFS event] and the curves looked quite similar.² This is in the intent-to-treat population, which is both of cohort 1 and cohort 2, both the ones based on size and nodal status and the one based on central Ki67 level. Putting those together, they had about 31% reduction in DRFS. [IDFS and DRFS] are different ways of looking at the same thing.

An interesting thing here was that the numbers seem to be getting a little better. The hazard ratio was getting better with time.² It is helpful to see that treatment benefit is maintained past when [the therapy ended]. It wasn’t that you stop the drug and everybody started to relapse. Two months after you stop the drug, there still seems to be benefit that’s persisting after that, which is nice to see and it’s what we’ve seen with hormone treatment anyway. If you stop when patients finish adjuvant treatment, then at 5 years, 7 years, 8 years, there seems to be some potential benefit.

Now, this leaves the question about whether more than 2 years [of treatment] would be better, but 2 years was chosen for these trials. Other trials are using different intervals.

_REFERENCES:

_{1. Johnston SRD, Harbeck N, Hegg R, et al. Abemaciclib combined with endocrine therapy for the adjuvant treatment of HR+, HER2-, node-positive, high-risk, early breast cancer (monarchE). J Clin Oncol. 2020;38(34):3987-3998. doi:10.1200/JCO.20.02514}

_{2. Harbeck N, Rastogi P, Martin M, et al. Adjuvant abemaciclib combined with endocrine therapy for high-risk early breast cancer: updated efficacy and Ki-67 analysis from the monarchE study. Ann Oncol. 2021;32(12):1571-1581. doi:10.1016/j.annonc.2021.09.015}

_{3. Mayer EL, Dueck AC, Martin M, et al. Palbociclib with adjuvant endocrine therapy in early breast cancer (PALLAS): interim analysis of a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2021;22(2):212-222. doi:10.1016/S1470-2045(20)30642-2}